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ARTICLE IN BRIEF

WASHINGTON, DC—Weight control may seem to depend primarily on willpower, the province of the frontal lobes, but the hypothalamus and other brain regions exert a powerful effect on appetite, metabolism, and adiposity, which in turn affect the health of the brain itself, according to presentations at the recent Society for Neuroscience meeting here.

Even the hippocampus, known primarily for its role in learning and memory, contains receptors for leptin, insulin, cholecystokinin (CCK), and other substances known to play a significant role in appetite regulation, according to Deborah Clegg, PhD, associate professor of internal medicine and clinical nutrition at University of Texas Southwestern Medical Center in Dallas.

“We know those players are critical in the hypothalamus and even in the hindbrain, but their role in body weight regulation in the hippocampus is very much understudied,” Dr. Clegg told Neurology Today. “I think leptin has a huge role in the hippocampus, but we just don't know what it is yet.”

One possibility is that leptin, insulin, and CCK promote neurogenesis in the hippocampus, “but that's just a guess,” Dr. Clegg said.

She cited the case of Henry Gustav Molaison, the patient known in the medical literature as H.M., who had virtually his entire hippocampus removed in 1953, at the age of 27, in an effort to control his intractable epilepsy. The surgery left him unable to form new memories, including, apparently, any memory of having eaten recently. If presented with another full meal minutes after finishing one, he would eagerly eat it, as though unaware of his full stomach. If presented with a third meal, he would eat that too.

Dr. Clegg and her colleagues noticed that rats with hippocampal damage also ate more than normal rats, perhaps because the hippocampus plays a role in normal inhibition of eating.

“The hippocampus is a critical site for memory processes that could contribute to the inhibition of eating,” she said. “We inhibit eating either by stopping when we're full, or by using willpower to not start in the first place. H.M. had a problem with both. He had a hard time remembering that he had just eaten, so he could not exercise willpower to stop himself from eating again, and he had a hard time experiencing feelings of satiety.”

While impaired hippocampal–dependent memory processes may be contributing to overeating and weight gain, the high-fat diet common in Western societies may also be damaging the hippocampus, apparently by causing the blood-brain barrier to become permeable, according to Dr. Clegg.

“Animals on a high-fat diet get a leaky blood-brain barrier, and it appears most leaky at the level of the hippocampus, so one idea we have is that perhaps peripheral cytokines or chemokines or inflammatory processes have the ability to get into hippocampus and impair typical signaling pathways,” Dr. Clegg said. “Also, if the blood-brain barrier becomes leaky at the hippocampus, perhaps environmental toxins such as arsenic can get in and impair normal function, which could cause obesity to occur.”

INSULIN SIGNALING, COGNITIVE FUNCTIONS

Insulin signaling in the hippocampus may also modulate memory and other cognitive functions, according to Ewan C. McNay, PhD, assistant professor of psychology at the University of Albany. The insulin resistance that comes with aging may reduce the ability of neurons to utilize glucose, making the brain vulnerable to dysfunction.

“In the Alzheimer's brain, for instance, there's often plenty of fuel available, but metabolic processes themselves are down-regulated,” he said in an interview with Neurology Today. “Hypometabolism means you're failing to have sufficient neural metabolic activity to optimally process cognitive tasks.”

As he and colleagues showed in a 2010 paper in Neurobiology of Learning and Memory, delivery of insulin to the rat hippocampus enhances spatial memory, while blocking insulin in the hippocampus impairs memory. They concluded that insulin resistance in the brain “may underlie the cognitive deficits commonly reported to accompany type 2 diabetes.”

Dr. McNay reported on an experiment with rats that showed an inverse correlation between glucose supply in the hippocampus and performance in a maze. “The task's demands exceed the glucose supply to the rat's hippocampus,” Dr. McNay said. “When the rat's brain glucose levels drop, its performance in the maze declines.”

The glucose supply in the hippocampus of an older rat, burdened with poorer metabolic regulation, drops even more. Providing glucose helps, as it does in humans, where a glucose-sweetened drink enhances cognitive performance, but the added glucose produces an inverted U-shaped curve — glucose causes performance to improve at first, but in excess produces too much neural excitation, causing performance to drop again.

Insulin acts in exactly the same way — supplying extra insulin rapidly boosts brain function, but giving too much reverses the benefit. This, too, has been confirmed in human studies, where intranasal insulin has seemed to ameliorate deficits seen in patients with Alzheimer disease.

“Acutely, hypoglycemia is never good because it prevents you from having sufficient glucose, but the consequences of a history of hypoglycemia can in fact be beneficial because the brain adapts,” Dr. McNay said. “If you're starving, your body adapts by storing fuel more efficiently and slowing the metabolism so it burns less. Your brain does the same thing. Being hypoglycemic, your brain up-regulates its transport capacity so that in the future you'll be better able to get glucose to the brain. Glucose transporter proteins are up-regulated, providing a bigger pipe, basically, for supplying glucose to the brain.”

That is why Dr. McNay believes that the recurrent hypoglycemia experienced by diabetics may not necessarily be deleterious. In a 2010 article in Physiology & Behavior, Dr. McNay and a colleague suggested that “the brain responds to recurrent hypoglycemia by increasing support for cognitive functions, and in particular by enhancing fuel supply, resulting in improved cognitive performance which may extend across large portions of the lifespan.” As a result, recurrent hypoglycemia, a frequent side-effect of intensive diabetes therapy, “appears to benefit cognitive function in ways that may also be produced by calorie restriction,” they concluded.

As he showed during his presentation, even a single weekly episode of hypoglycemia makes an old rat perform like a young rat cognitively.

“I think the evidence is pretty strong that the impact of repeated starvation, caloric restriction, intermittent fasting, whatever you call it, is beneficial, or certainly not harmful,” Dr. McNay said. “As long as total caloric intake is maintained down, and the exercise level is maintained up, the side-effects may not be negative.”

One potential problem, however, is that repeated food deprivation causes the body to slow its metabolism, which can lead to weight gain and lethargy unless overruled by close dietary control and vigorous exercise.

“Just go to the gym,” Dr. McNay said. “We know that insulin sensitivity, which can be increased by exercise, is tightly linked to both metabolic regulation and cognitive performance. It's also linked to removing amyloid from the brain. So rather than worrying about fasting and caloric restriction, the easier answer is go exercise more.”

EPIGENETIC EFFECTS: DIET AND EXERCISE

Although calorie restriction promotes cognitive function, similar benefits can be achieved through diet and exercise, according to Fernando Gómez-Pinilla, PhD, a professor in the departments of neurosurgery and physiological science at the David Geffen School of Medicine at the University of California, Los Angeles. Diets rich in omega-3 fatty acids, for example, can reduce vulnerability to mental disorders and the effects of brain trauma, while those rich in saturated fats and sugars do the opposite, according to Dr. Gómez-Pinilla.

In a poster, he and his colleagues reported on their research showing that diet and exercise can produce epigenetic effects that influence cognitive function and emotions. Diet, for example, influences the production of docosahexaenoic acid (DHA), an omega-3 fatty acid that is a component of neuronal plasma membranes and crucial for the regulation of neuronal signaling. DHA deficiencies produce anxiety-like behavior in rat pups, they reported in a summary of their work, and result in a reduction of brain-derived neurotrophic factor (BDNF) signaling, which “imposes a risk factor for anxiety-like behaviors in adult life, in conjunction with affecting chromatin remodeling (global methylation) in the hippocampus.”

Drawing on his 2008 paper in Nature Reviews Neuroscience, Dr. Gómez–Pinilla explained that the epigenetic regulation of BDNF may be the mechanism through which diet and exercise modulate cognitive function. Exercise-induced BDNF contributes to synaptic plasticity, for example, and vagal nerve stimulation, which alleviates depression, produces epigenetic changes that boost BDNF.

“Diet and exercise have an influence on metabolic homeostasis,” he said during his presentation. “There has been a significant change in diet habits in the last 20 years, and the repercussions for the brain have resulted in an increased risk for neurological and psychiatric disorders.”